Integrating CAR-T therapy with PD-1/PD-L1 blockade: Mechanisms, synergy, and optimized strategies in NSCLC

Non-small cell lung cancer (NSCLC) presents persistent challenges in immunotherapy, as the clinical benefit of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors is frequently constrained by intrinsic and acquired resistance. Central contributors include impaired antigen presentation, T cell exclusion, and the accumulation of immunosuppressive populations that collectively establish a "cold" tumor microenvironment (TME). These mechanisms dampen cytotoxic CD8⁺ T cell function and limit the durability of PD-1/PD-L1 blockade. Our single-cell RNA-seq reanalysis further supports that exhausted CD8⁺ T cells and regulatory T cells (Tregs) are enriched in non-responsive NSCLC, accompanied by compensatory upregulation of alternative checkpoints. Given these limitations, complementary approaches such as chimeric antigen receptor T cell (CAR-T) therapy have shown promising potential to overcome PD-1/PD-L1-driven immunosuppression. Although CAR-T cells are effective in hematologic malignancies, their activity in NSCLC is limited by antigen heterogeneity, dysfunction induced by the TME, and inhibitory signaling mediated by PD-1. Integrating checkpoint blockade with CAR-T therapy offers a rational strategy: PD-1/PD-L1 inhibitors can alleviate exhaustion and remodel the TME, and CAR-T cells provide potent, antigen-specific cytotoxicity and enhance infiltration into poorly immunogenic tumors. This review summarizes mechanistic intersections between PD-1/PD-L1 signaling and CAR-T cell biology and discusses emerging synergistic strategies, including multi-target CAR constructs, engineering strategies targeting the TME and tumor metabolism, and localized or self-delivered checkpoint blockade. We also highlight safety-oriented designs, including logic-gated CARs and inducible safety switches, which aim to mitigate cytokine-related or on-target/off-tumor toxicities. Finally, we outline how computational modeling and machine learning may accelerate the design, optimization, and personalized application of these combination approaches. Together, the integration of CAR-T therapy with PD-1/PD-L1 inhibition represents a promising framework for overcoming resistance and improving outcomes in NSCLC.